Project Summary/Abstract The overall goal of this proposal is to understand how organisms as diverse as humans and the fruit flies use the same molecules to determine how large their organs will grow. The specific focus of this application is a protein that promotes growth called Yorkie. In our cells it is called Yap1, however it performs the same job in both species. When Yorkie/Yap1 is `active' in cells, it tells the cells to grow and divide, and thus generates many new cells. This makes tissues larger since they have more cells, but it can also lead to the growth of a cancerous tumor. We know a bit about how Yorkie/Yap1 become `active' but not enough to reliably predict when and where this happens, or how it promotes cancer when it becomes `active' all the time. We have found another protein that physically binds to Yorkie called Taiman, and we think Taiman may be key to understanding when and where Yorkie gets activated. Taiman itself has to get `activated', but in this case we know more about this happens. Taiman gets `activated' by the fly equivalent of the human sex hormones estrogen and testosterone. We think that when these hormones `activate' Taiman that they also activate Yorkie, and that this is an important way receive signals to grow and divide. The experiments we propose will address this hypothesis in a number of ways. We will test our idea that some cells can make their own fly `sex hormone' (called ecdysone), and that how much ecdysone they make controls when and where Taiman and Yorkie get activated in adolescent flies. This kind of patterned `activation' of Yorkie/Yap1 may be part of why we grow organs & appendages in the right places each time an embryo develops into a newborn baby, and by extension how inappropriate `actvation' of Yorkie/Yap1 at the wrong place and time can drive disease. We will also test another idea that cells with `activated' Yorkie and Taiman actually think they are part of a healing wound and start the process of regeneration to fill in the missing cells and tissue. Although we use flies to study these ideas, we remain confident that much of what we learn will teach us about how all of the proteins work in our cells.